Molecular shuttling

Julie Last uses an atomic force microscope to image the travels of receptor-lipids on an artificial cell membrane.

May 6, 2002—Sandia National Laboratories researchers witnessed molecular
movements recently that could evolve into some of the first useful tools at future
nanoconstruction sites, where proteins might be shuttled from place to place in tiny
chemical wheelbarrows or built upon molecular scaffolding. The insights might also
help create cell-sized ambulances that could travel to and selectively repair or destroy
diseased cells in a human patient's body.

Using improved observational methods, the Sandia team watched as huddled
receptor—or grabber-molecules on a man-made cell membrane rapidly dispersed
across the membrane when they latched onto free-floating ligands (chemical particles),
then rehuddled when the ligands were removed. The behavior mimics biological
reactions at the cell level, such as immune system response to viral particles, says
Darryl Sasaki of Sandia. The work is based on previous research at Sandia to create
metal-detecting sensors based on chemical recognition events.

"When they bind to the ligand, they each race away from their nearest neighbor," says Sasaki. "When the ligands are removed,
they race back to where they were."

Molecules with Memories

The researchers created an artificial cell membrane made of "phospholipid bilayers"—rows of long molecules that, like empty
soda bottles bobbing on water, self-organize into an orderly heads-up/tails-down formation. They implanted this lipid film with
lipids carrying tall receptor headgroups—pincher- or lasso-shaped structures that chemically grab onto free-floating ligands.

Then they watched as the receptors reacted to the addition of metal ions. At rest the receptor-lipids pooled into aggregate zones
between islands of shorter receptor-less lipids. But when metal ions (lead or copper) were added to the solution, the headgroups
latched onto the ions, and ZIP!—the receptor-lipids dispersed across the membrane surface as their newly acquired electrostatic
charges caused them to become mutually repulsed. When the metal ions were removed, the wayward receptor-lipids retraced
their steps and regrouped into the same aggregated pools. The process was performed repeatedly on the same membranes with
the same result-reversible reorganization.

Sasaki believes the trails the receptor-lipids follow and the pools they return to correspond, quite literally, to the paths of least
resistance on the membrane's surface-areas where the lipid film is more liquid than solid, allowing the traveling lipids to flow like
water.

Tracking Tiny Travelers

Although producing such chemical recognition events on an artificial membrane is not an achievement in itself, examining them
with such fidelity is, says Sasaki. The Sandia team used novel microscopy and spectroscopic techniques to make the first
documented observations of receptor-lipids dispersing and regrouping.

Fluorescent pyrene tags were attached to the tails of the receptor-lipids to aid in tracking their travels on the membrane. When
the receptors were aggregated—as seen using fluorescence spectroscopy—the huddles appeared bright. When the receptors
were dispersed, their fluorescent signals were dim.

In addition, the team used an atomic force microscope to map the topography of the lipid membrane, identifying locations of the
tall receptor headgroups that towered 8 angstroms (about one billionth of a meter) higher than the tops of the membrane lipids.
These observations provided unprecedented clarity about the locations of the receptors in both the dispersed and aggregated
states, Sasaki says.

"We've been able to characterize films as they change their properties at both the macroscale and nanoscale," he says. "It's the
first time such a dynamic molecular system has been imaged this way."

The observations will provide scientists with a better understanding of chemical recognition on cell-like membrane systems.

Nanotech's Toolbox

Perhaps more tantalizing, he says, are the possibilities the new understandings might bring to the nanotechnology community's
growing toolbox.

"The idea of using chemical recognition to form specific structures in the membrane may be a potent tool to aid in the
development of controllable nanoscale architectures," says Sasaki.

If receptor headgroups propelled to and fro by chemical recognition events can be enlisted to hoist molecules and proteins and
deposit them in planned locations, he says, designing and building nanosized structures, such as single-molecule-wide wires,
might be possible. And the receptor-lipids' tendencies to follow preferred pathways offers promise for engineered construction
of nano-railroad tracks along which a variety of molecular cargos could be recurringly moved, perhaps aboard motor-protein
railcars, he says.

If researchers can learn to control these routes, two- or three-dimensional lipid scaffolds might be designed upon which proteins
could be laid down to build nanoscale electronic or photonic circuits. Nano-switching structures might be designed that
self-construct and self-destruct based on chemical recognition events.

And researchers have long sought to build cell-like pods that, when injected into a person's blood stream, would recognize
diseased cells and release a drug to destroy those cells selectively.

"By harnessing even a fraction of the capability of cellular membrane recognition systems, it may be possible to build unique
sensor systems that are not only rapid and specific in response but also are innately biocompatible," adds Sasaki.—by John
German

Sandia National
Laboratory is a multiprogram laboratory operated
by Sandia Corporation, a Lockheed Martin company,
for the U.S. Department of Energy. With main facilities
in Albuquerque, New Mexico, and Livermore, California,
Sandia has major R&D responsibilities in national
security, energy and environmental technologies,
and economic competitiveness.

Author: John German is
Media Relations Assistant Team Leader at Sandia
National Laboratory. He specializes in topics on
robotics, criminal justice/law enforcement, counterterrorism,
aircraft safety R&D, weapons nonproliferation, critical
infrastructure issues, engineering sciences, simulation
and testing, and nuclear power issues. For more
science news, visit Sandia
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